The 1st IAS Conference on HIV Pathogenesis and Treatment

The International AIDS Society (IAS) hosted its first conference on HIV pathogenesis and treatments in Argentina, on July 8-11, 2001. The conference focused on the clinical care of people living with HIV disease. The goals of the IAS are to improve the overall quality of life of persons infected with HIV and to improve access to health care in underdeveloped countries.

In South America only four countries are supplying treatments to their HIV-infected population which total more than 1.5 million men, women and children. Most HIV cases go undiagnosed in those countries that choose not to recognize the epidemic. With every death there is a silent scream of the unfairness and inequalities of governments who do not educate, treat and prevent the spread of HIV infection.

To date, more than 60 million people worldwide have been infected with HIV since the beginning of the epidemic. Twenty two million of them have already died of AIDS (abstract PL3). The continually spreading HIV epidemic is leading to national catastrophes with breakdowns of infrastructures, economies, and national and regional securities. Furthermore, only about 10 percent of those infected have benefited from any therapeutic gains. There continues to be a dramatic inequality between developed and undeveloped countries, as well as between the rich and the poor in access to both health care and drug therapy.

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As the conference progressed, it became apparent that due to the complexities and cost of current ARV (antiretroviral) combinations, it leaves most of the world without a solution to the AIDS epidemic. Current prevention strategies have produced results that continue to be elusive. Prevention can only be accomplished when scientists, community leaders and workers can develop sustainable programs by making long-term commitments, developing infrastructure, and training a second generation of scientists and leaders. Programs implemented in underdeveloped countries will fail, without a research and care infrastructure. Issues to be considered are: effective treatment, metabolic complications, under-suppression of viral replication leading to the potential transmission of mutated virus, and cost.

Clearly one of the most disturbing posters was on AIDS-associated hospitalization in the HAART era. Universal access is not universally protective (abstract 313). In some countries, the most common opportunistic infections are among those which are preventable with prophylaxis (abstracts 37b, 38). Lifestyle, lack of patient education and deficits in health care systems are just a few of the issues that pose challenges in underdeveloped countries. In countries where resources are limited, eligibility for ARV is based on total lymphocyte counts (not T-cells); or clinical markers such as thrush (abstract 314) are indicators of when ARV (if available) or preventative therapy are started.

When Will We Know When?

When should ARV therapy be started continues to be a question that plagues clinicians and patients alike. Scattered reports addressing the question of which ARV combination is superior; a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen continues to be debated (abstracts 1, 6, 7). Based on the availability of the literature, PI-containing regimens are more successful in individuals with CD4 T-cells less than 50 cells/mm3 and higher viral loads, which were again validated in several studies present at IAS (abstracts 1, 648, 649, 645). Protease provides a greater genetic barrier with more mutational changes required to develop viral resistance. Another important factor is that highly active antiretroviral therapy (HAART) that contains a protease may penetrate the lymph node reservoirs more so than non-PI regimens (abstract 28). The opposing viewpoint is to start a non-nucleoside reverse transcriptase (NNRTI) or a triple nucleoside regimen (containing abacavir) as initial therapy because of low pill burden, simpler dosing, and an increase in half-life that may support once a day dosing. Improved tolerability with a reduction in metabolic changes and major increases in lipid profiles may also be an advantage (abstracts 490, 495, 501-502). However, the NNRTI containing regimens have a very narrow genetic barrier, which can lead to the development of rapid viral resistance.

Although the morbidity and mortality of HIV infection has dramatically diminished because of ARV, metabolic complications and concerns of the development of ARV resistance have researchers and clinicians not only questioning the appropriate time to start therapy, but whether scheduled treatment interruptions (STI) may have added benefits in both adherence (abstracts 442-445) and immunologic response. [Editors Note: HIV mortality may be diminished, however it seems to us that death due to medication side-effects is on the rise (e.g., heart attacks, lactic acidosis, liver failure, pancreatitis, etc.)] STI may lead to a reduction in the risk of developing metabolic complications with prolonged use of PI-containing regimens (abstract 56). The STI strategy must continue to be looked at in randomized controlled clinical trials.

Direct observation therapy (DOT) may improve virologic response (abstracts 426-428), however it may not be very cost-effective. Induction and maintenance with ART is gaining in popularity, hitting the virus hard with a PI-containing regimen to reduce viremia until the subject's viral replication is below the lower limit of detection and then switching. Switching may include the substitution of a PI for an NNRTI or abacavir to decrease toxicity, pill burden, dosing frequency and improve adherence (abstracts 58, 418-425). Another approach to simplification may include changing ARV to once-a-day dosing after the HIV-infected individual has obtained complete viral suppression (abstracts 59, 60).

Looking at why ARV therapy fails individuals may include high toxicities, high pill burden, and efficacy of the therapy prescribed (abstracts 698-704). Intracellular concentration of ARV (NRTI) poses an unique and difficult problem; it's expensive and technically not available. However, it appears to be an important direction that will be pursued in the future (abstracts 25, 30, 33).

Therapeutic drug monitoring (TDM) is becoming more popular in monitoring random levels of a PI or NNRTI and adjusting the levels up or down depending on whether each individual patient's trough is too low and may allow resistance to develop or too high leading to an increase in toxicity. ["Trough" means the lowest effective amount of drug circulating in your body.] Equally important is the development of a drug assay that has the ability to measure drug concentrations in sanction sites such as the genital tract (abstract 25).

Novel new medications were limited to mozenavir (DMP 450) a protease inhibitor developed by Merck, which is in current clinical trials in combination with stavudine and lamivudine (abstract 2). The major toxicities are gastrointestinal affects such as nausea and diarrhea, which only occurred in less than 12 percent of the study population. Atazanavir (TAZ) is the new name for the BMS compound, which appeared to be well tolerated in clinical trials with little to no impact on lipid profiles and very few grade 3 or 4 toxicities (abstracts 5, 350).

Tipranavir is a PI that appears in vitro to be effective against current resistant strains of virus. It is synergistic with the currently available PIs, NRTIs and NNRTIs and will probably be enhanced with the use of ritonavir (abstract 3). Lopinavir with a little bit of ritonavir (LPV/r) now known as Kaletra had data on several naive and salvage trials. Those individuals who's viral load rebounds above baseline (baseline is the viral load before treatment) cannot be attributed to having Kaletra specific mutations. However, specific mutations have not been well characterized for Kaletra (abstracts 129, 444, 672).

Lipodystrophy (LDS), also referred to as the metabolic complications of HIV disease, and its treatment continues to be at the forefront of research (abstracts PL11, 482-523). Data was presented about the psychological impact of LDS (abstract 497), the efficacy of a multidisciplinary approach in treating patients with LDS (abstract 499) and surgical interventions (abstract 500). LDS may develop in HIV-infected individuals due to the increase in endogenous glucose production of both peripheral and hepatic insulin resistance (abstract 495). Women are at a higher risk of developing LDS [LDS is the bad cholesterol] (abstract 502). Gynaecomastia is another immune reconstitution disease affecting both women and men (abstract 650).

Viral hepatitis and drug-related (hepato) liver-toxicity continues to pose problems with an increase in morbidity and mortality (abstracts 541-549, 556). Results from the use of ribavirin and alfa interferon continue to be disappointing with decreased tolerability and viral rebound after discontinuation (abstract 550-555). Little data was available on advances in an HCV vaccine.

Tuberculosis (TB) and HIV are still quite commonly found together as a co-infection especially in third world countries (abstract 451). This co-infection may influence the ability of the patient to tolerate ARV (abstract 456) and TB treatment as well as the potential drug interaction between anti-tuberculosis medication and ARV therapy (abstracts 454-459). New concerns arise with the increasing development of world wide multidrug resistant TB (abstracts 464-465) and the relevance of direct observational therapy (DOT) (abstract 467).

Some Things Never Change

Once again very little data was presented looking at gender differences between women and men in response to HIV infection, manifestations of opportunistic infections and ARV treatment (abstracts 260, 350, 378). Most of the abstracts presented studies conducted on the female genital tract (abstracts 260, 350, 378, 505, 428, 762, 796) or mother-to-fetal transmission, which although are important issues, continues to miss the pressing issue about gender based difference in women from men (most of the drugs available for treatment have been studied on men with only 8-12 percent of the current clinical trials participants being women). Mother-fetal transmission continues to be an issue in underdeveloped countries; several posters showed that providing ARV to women during pregnancy or active labor has dramatically decreased the rate of HIV transmission to the fetus (abstracts 755-770). However, breast-feeding continues to provide a potential route of HIV transmission to infants, and continues to be essential in those countries that have no other nutritional alternative. A few pilot studies are proposing to look at administering ARV to infants during the first 6 months of breast feeding to evaluate the effectiveness of ARV during this time period.

African Proverb

In conclusion, designing prevention interventions, screening those individuals in the population who are at risk for HIV infection and then determining the appropriate time to initiate therapy, encouraging adherence to medication regimens, monitoring for ART toxicities, avoiding the emergence of resistance and providing primary prophylaxis for opportunistic infection, as well as maintaining adequate nutrition is an ongoing process in developed countries. Treating people in developing countries cannot be a laboratory diagnosis, but a clinical diagnosis. It has become apparent over the past few years that minimizing the destructive nature of the epidemic will require partnerships between the public and private sectors, between developed and undeveloped countries.

Currently six different bills are proposed to the United States Congress addressing funding for developing countries to create the infrastructure necessary to fight the AIDS epidemic globally.

The development of a vaccine is imperative in order to contain this epidemic.

In closing, I'll leave you with this African proverb:

The best time to plant a tree is 40 years ago;
And the next best time is now.

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